11-Substituted erythromycin B derivatives

ABSTRACT

Covers 11-substituted erythromycin B derivatives having a formula selected from the group consisting of:   WHERE R is selected from the group consisting of lower alkyl and -CHR3SR4 where R3 and R4 are loweralkyl, and R1 and R2 are hydrogen or loweralkyl and;   WHERE R1, R2 and R3 are as before defined. Said erythromycin derivatives are useful as antibiotics or as intermediates useful in preparing other useful antibiotic compounds.

United States Patent 91 Jones et al.

[451 May 20, 1975 ll-SUBSTITUTED ERYTHROMYCIN B DERIVATIVES [75] Inventors: Peter Hadley Jones, Lake Forest;

James Bruce McAlpine, Libertyville; Jeanne Marie Pauvlik, Waukegan; Thomas John Perun, Libertyville, all of I11.

[73] Assignee: Abbott Laboratories, North Chicago, Ill.

[22] Filed: June 21, 1973 [21] Appl. No.: 372,386

Primary Examiner-Johnnie R. Brown Assistant Examiner-Cary B. Owens Attorney, Agent, or FirmRobert L. Niblack [5 7] ABSTRACT Covers 1 l-substituted erythromycin B derivatives having a formula selected from the group consisting of:

where R is selected from the group consisting of lower alkyl and -Cl-lR SR where R and R are loweralkyl, and R and R are hydrogen or loweralkyl and;

EPEEEB where R,, R and R are as before defined.

Said erythromycin derivatives are useful as antibiotics or as intermediates useful in preparing other useful antibiotic compounds.

5 Claims, No Drawings 11-SUBSTITUTED ERYTHROMYCIN B DERIVATIVES DESCRIPTION OF THE INVENTION (de sosamine) cladinose cmocn (erythronolide) In this formula, when R R and R represent hydrogen and R represents hydroxyl, the structure illustrated is erythromycin A. When R is, however, also hydrogen, the structure of erythromycin B is illustrated.

Erythromycin, as will be noted from the formula, comprises three cyclic fragments. These fragments are referred to respectively as cladinose, desosamine and erythronolide. The positions on the cladinose ring are indicated by double primed numbers; the positions on the desosamine ring by single primed numbers; while positions on the erythronolide ring are indicated by unprimed numbers In order to prepare the erythromycin derivatives here one may start with either 4" loweralkanoyl erythromycin B or 2', 4" diloweralkanoyl erythromycin B. The 2', 4" diloweralkanoyl, l l-O-a-dialkylsulfide erythromycin B group of derivatives are then formed by reacting a dialkyl sulfoxide with one of the above erythromycins in the presence of a lower acid anhydride. This product in turn inay be treated with a lower alcohol to produce the ll-O-a-dialkylsulfide erythromycin B derivatives. The lower alcohol acts to remove the alkanoyl groups. The ll-O-a-dialkylsulfide erythromycin B derivative is then reduced with an appropriate reducing agent such as Raney Nickel to produce a mixture of the cyclic acetal of erythromycin B and the ll-alkoxy erythromycin B derivative. These are then separated from one another.

In order to produce the cyclic acetal erythromycin derivative free of admixture with ll-O-alkyl erythromycin B, an 1 l-O-a'dialkylsulfide erythromycin B derivative is reacted with mercuric chloride mercuric oxide.

The following examples illustrate fully the preparation of the derivatives of the invention:

Example I 2-O-Acetyl-4' -O-formyl-l l-O-methylthiomethyl erythromycin B en, en,

4"-O-Formyl erythromycin B (2.0 g., 2.7 mmoles.) was combined with 20 ml. of dimethylsulfoxide and 14 ml. of acetic anhydride and allowed to stand overnight. The mixture was then poured into cold, 10% sodium carbonate and extracted three times with chloroform.

I The combined'chloroform extracts were washed once with 5% sodium bicarbonate and once with water. After drying over sodium sulfate, solvent was removed to give 2.32 guof crude product, shown by NMR and TLC to be the desired product.

A sample was chromatographed on Sephadex Ll-l-20 in chloroform-hexane 1:1. The peak fractions were combined, concentrated and the residue was recrystallized from benzenehexane mixtures to give 2'-O-acetyl- 4"-O-formyl-l l-O-methyl-thiomethyl erythromycin B containing one molecule of dimethylsulfoxide of crystallization as evidenced by NMR and microanalysis.

The product analyzed as follows:

Analysis calculated for C I-I NO S C H SO M.W. 926.1; M.P. 127 C.

ll-Q-Methylth iometlyl erythromyc in B cmscnp 2 -O-Acetyl-4 '-O-formyl-1 l-O-methylthiomethyl erythromycin B from Example I was dissolved in 100 ml. of methanol. To this solution was added 50 ml. of 5% sodium bicarbonate, and the mixture was stirred for 24 hours. Some methanol was removed under vacuum on the rotary evaporator, water was added to the mixture, and the mixture was extracted three times with chloroform. The combined chloroform extracts were washed with water, dried over sodium sulfate, and solvent was removed to give 2.06 g. of crude product, shown by NMR and TLC to be desired product.

A sample recrystallized from ethanol had an M.P. of 101 103 C.

Analysis calculated for: C H- NO S, M.W. 778.065

Example 111 9,11-Q-Mechz1ene erzthrcmzc'in 8-6 9-hemiaceta1 ll-O-Methylthiomethyl erythromycin B (1.0 g., 1.4 mmoles.) was dissolved in a solution of 1.0 ml. of water and 30.0 ml. of acetone. When all of the 11-0- methylthiomethyl erythromycin B had dissolved, 1.0 g. I

of mercuric oxide and 1.5 g. of mercuric chloride were added and the resulting mixture was stirred for 3 hours. After stirring, the mixture was filtered and the filtrate was extracted three times with chloroform. The combined chloroform extracts were washed once with 5% sodium bicarbonateand once with water. After drying overisodium sulfate, solvent was removed on the rotary evaporator to give 1.16 g. of product. This product was treated with methanol 5% sodium bicarbonate for several days and then extracted three times with chloroform. The combined chloroform extracts were washed with water, dried over sodium sulfate, and solvent was removed to give 0.97 g. of product. Crystallization from methanol-water gave 360 mg. (35%) of clean, white crystalline product (one spot on TLC).

The product analyzed as follows:

Analysis calculated for: C d-1 N0 M.W. 729.96; M.P. 185 186 C.

1 l-O-Methylthiomethyl erythromycin B (1.089 g.) in ethanol (100 ml.) was treated with 30 ml. of a thick ethanol suspension of Raney Nickel and the mixture was heated under reflux for minutes then allowed to cool and filtered. The filtrate was concentrated and the residue was passed through a counter current distributor charged with the lower (stationary) and upper (mobile) phase from n-heptane (25 parts), benzene (50 parts), acetone (15 parts), isopropanol (10 parts), aqueous potassium phosphate buffer (pH 7.0, 0.01 M in P0 5 (25 parts). Upper phases were removed and collected after 200 transfers. Initial fractions collected contained 9,1 l-O-methylene erythromycin B6,9- hemiketal (NMR spectrum identical with that of the sample as obtained in Example 111 above). Subsequent fractions contained ll-O-methyl erythromycin B (401 mg.) which was further purified by chromatography on Sephadex Ll-l20 in chloroform-hexane 1:1 to give 213 mg. of product.

The product analyzed as follows:

Analysis calculated for: C H NO ll-O-n-Butyl erythromycin B 4-O-Formyl erythromycin B (2.7 g.) in tetramethylenesulfoxide (25 ml.) and acetic anhydride (10 ml.) was allowed to stand at room temperature for 18 hours. The mixture was poured into ice cold sodium bicarbonate solution l 1., 5%) and extracted with chlo- 6 roform (2x100 ml.). The combined extracts were where R is selected from the group consisting of lower washed with water and concentrated under vacuum. alkyl, Cl-l SCl-l CH SCI-I CH C1-I CI-I C1-l and The concentrate was passed down a column of Sephaa 4 Where 3 and 4 are lower y and 1 dex Ll-I-20 in chloroform-hexane 111. Initial fractions and R2 are hydrogen or lower alkanoyl and;

were concentrated and allowed to stand in methanol 5 for one week. Methanol was removed and the residue was passed down a column of Sephadex LH-20 in chloroform-hexane 1:1. Initial fractions were concentrated Fmula n and treated with Raney Nickel (ca. 30 g.) in ethanol (100 ml.) under reflux for ninety minutes. The mixture N CH was cooled and filtered through a pad of celite. The fil- R O 3 2 trate was concentrated and passed down a column of 1 Sephadex LII- in chloroform-hexane 1:1. Later frac- I/LCH tions were concentrated to give ll-O-n-butyl erythro- 9 3 mycin B. Mass spectrum m/e 773. I5 0 CH Analysis calculated for: C I-1 N0 3 CR2 Microanalysis Theory Found 3 3 c 63.6 63.7 20 H 9.8 10.0 N 1.8 1.8 O 24.8 25.2

The compounds were then tested for their activity against gram-positive and gram-negative bacteria in an where Rh R2 and R3 are as b f d fi d agar dilution test. Results are given in MIC values (min- 2. The derivative of claim 1 wherein R is methyl, and imum inhibitory concentrations) expressed in micro- R and R are hydrogen in Formula I. grams/ml. as follows: 3. The derivative of claim 1 wherein R is TABLE I MIC (in Meg/ml) Organism Ex. I Ex. II Ex. III Ex. IV Ex. V

Staphylococcus aurcus ATCC 6438? 1.56 Staphylococcus aureus 9144 1.56 0.78 0.78 Staphylococcus aurcus Smith 25 0.78 0.78 0.78 Staphylococcus aureus Smith ER 100 100 100 100 Staphylococcus aureus Quinones 100 100 50 100 Staphylococcus uureus Wise 155 100 100 5O 100 Streptococcus faecalis 10541 6.2 0.2 0.2 0.39 0.78 Escherichia coli .luhl 100 100 100 100 Klebsiclla pneumoniae 10031 100 25 12.5 12 5 100 Proteus vulguris Abbott .1] 100 100 100 100 Proteus mirabilis Finland N0. 9 100 100 100 100 Salmonella typht'muriunt Ed No. 9 100 100 100 100 Shigella sonnet 9290 100 50 100 Pscudomonas aerugt'nosa BMH No.10 100 100 100 100 100 Streptococcus pyogenes Roper 100 100 50 100 Haemopht'lus inflttcnzae 9334 100 25 50 50 Haemopht'lus influcnzae Brimm CSF 50 25 Haemopht'lus influenzac lll. 25 25 Huemophilus influenzae Patterson 25 12.5 Haentopht'lus influcnzae Shemwell 25 12.5 Haemopht'lus influenzae Terry 25 12.5 Bacillus subtt'lt's No. 10707 (U. of 111.) 1.56

We claim: 0 1. An ll-substituted erythromycin B derivative se- H lected from the group consisting of: CH -C- and R is Z S hydrogen in Formula II.

3 N(CH )2 p O R CH 0 1 3 R0 o 0 CH3 in Formula I.

3 CH3 4. The derivative of claim 1 wherein R and R are CH3 hydrogen in Formula I.

o 032 5. The derivative of claim 1 where R, R and R are CH3 I O 3 OCH3 

1. AN 11-SUBSTITUTED ERYTHROMYCIN B DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF:
 2. The derivative of claim 1 wherein R is methyl, and R1 and R2 are hydrogen in Formula I.
 3. The derivative of claim 1 wherein R1 is
 4. The derivative of claim 1 wherein R1 and R2 are hydrogen in Formula I.
 5. The derivative of claim 1 where R1, R2 and R3 are hydrogen in Formula II. 